Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof



United States Patent 3,218,328 HETEROCYCLIC AMINO PI-IENOXYACETIC ACIDS,ACID ADDITION SALTS AND QUA- TERNARY AMMONIUM SALTS THEREOF Seymour L.Shapiro, deceased, late of Hastings on Hudson, N.Y., by Florence M.Shapiro, executrix, Hastings on Hudson,- N.Y., Louis Freedman,Bronxville, and Harold Soloway, New Rochelle, N.Y., assiguors to US.Vitamin & Pharmaceutical Corporation, New York, N.Y., a corporation ofNew York No Drawing. Filed Feb. 18, 1963, Ser. No. 259,460 3 Claims.(Cl. 260-294) This application is a continuation in part of applicationS.N. 818,548 filed June 8, 1959, now abandoned.

This invention relates to heterocyclic amino substituted phenoxyaceticacid compounds in which the heterocyclic amino group is attached to thephenyl ring through a ring nitrogen atom, and includes correlatedimprovements and discoveries whereby novel compounds having usefulcharacteristics are provided.

A principal object of this invention is to provide novel heterocyclicamino substituted phenoxyacetic acid compounds, including the acids,esters, amides, salts, acid addition salts and quaternary ammoniumsalts.

Another object of the invention is to provide compositions which areparticularly effective for reducing the cholesterol level of blood,containing heterocyclic amino substituted phenoxyacetic acid compounds,esters, amides and related compounds.

In accordance with this invention, it has been determined thatphenoxyacetic acid compounds having a heterocyclic amine group attachedto the phenyl nucleus through a ring nitrogen atom are particularlyeffective as hypocholesteremic agents. The heterocyclic amine grouppreferably contains at least about four carbon atoms and may alsocontain other heterocyclic substituents, such as nitrogen, oxygen andsulfur, either as part of the ring or attached to other atoms which arepart of the ring. Preferably the heterocyclic amine group has from fourto ten atoms in the ring, of which from one to three, preferably one,should be heterocyclic atoms, the remainder being carbon atoms. Theheterocyclic amine group can be substituted in any position onthe'phenyl nucleus, ortho, meta or para to the oxyacetic acid group.

The alpha carbon atom of the acetic acid group attached through anoxygen atom to the phenyl nucleus can be substituted or unsubstituted.If substituted, it is preferably substituted with a lower alkyl grouphaving from 1 to 6 carbon atoms.

Suitable heterocyclic amino phenoxyacetic acid compounds of thisinvention are the phenoxyacetic acids and the esters and amides of thephenoxyacetic acids with lower alkyl alcohols, cycloalkyl alcohols,lower alkanolamines, ammonia and lower alkyl amines.

The phenoxyacetic acid compounds of this invention can be defined by thefollowing formula:

In the above formula, R can be hydrogen or a lower alkyl group havingfrom 1 to 6 carbon atoms, R can be selected from the group consisting ofhydroxy, lower alkoxy, cycloalkoxy preferably having from to 7 car-3,218,328 Patented Nov. 16, 1965 bon atoms, hydrazino, monoand diloweralkyl-hydrazino, amino of the formula and lower oxyalkyl amino of theformula wherein R and R, can each be hydrogen, lower alkyl, monoanddi-(lower alkyl)-amino-lower alkyl and aminolower alkyl [c.g. C H NH inthe above formula is a heterocyclic group, having from 4 to 10 atoms,preferably 5 to 7 atoms, in the ring, from one to three ring atomsthereof, preferably from one to two, being selected from the groupconsisting of nitrogen, oxygen and sulfur, at least one being nitrogen,the remaining ring atoms being carbon. The ring atoms can beunsubstituted or substituted with inert groups such as lower alkyl,hydroxy and carbonyl or keto oxygen, =0. The total number of carbonatoms in the group preferably does not exceed about 15.

It will be evident from the foregoing that the phenoxyacetic acidcompounds of'the invention are acids when R is OH, esters when R isalkoxy or cycloalkoxy or oxyalkylene, and amides when R is amino; Theterm acid compound is used generically herein to refer to all of thesesubgenera of the invention.

Thus, in the foregoing formula, R R and R can each be, for example,hydrogen, methyl, ethyl, n-propyl, isopropl, n-butyl, iso-butyl, t-butyland any of the pentyl and hexyl isomers. R can, for example, be hydroxy,methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxyand any of the isomeric pentoxy and hexoxy derivatives, cyclopentoxy,cyclohexoxy and cycloheptoxy, amino, monomethylamino, dimethylamino,monoethylamino, diethylainino, monoisopropylamino, diisopropylamino,mono-n-propylamino, di-n-propylamino, mono-n-butylamino,di-n-butylamino, mono-t-butylamino, di-t-butylamino, monopentylamino,dipentylamino, monohexylamino, dihexylamino, OCH CH -NH hydrazino,methyl hydrazyl, ethyl hydrazyl, propyl hydrazyl,

, 3 4 and GHQ-CH1 /-CH3 N/ NH(CH;) 'N fl,

- 5 GIL-0H, Thus N/ NH om-cg The following compounds are illustrative ofcompounds coming within the scope of the invention 7 1 o can be, forexample oncHflulmocgH5 v /CH2-CH1 1 n N NY 0 O-CH C-NH:

, /CHr-CH3 2% g a /N I CHI-CH:

in which the Q groups are alkylene groups containing 0 from one to aboutten carbon atoms, n 1s zero or one and g 0-0112 --NHO,H5

the total number of ring atoms in the group a GHQ-CH2 N\/ Q CHr-CH:ranges from about four to about ten. Representative (4) f0CHzONH(CHz)3N(CH GET-OH; 40" N/ 1 OHg-CH;

groups include GET-CH1 (5) I Fame-0 01115 CHz-CH, v

I CHPCHQ CHr-CE; CH 2 r t CH2- H:

Gin-0H: on CH CH (6) 1? N/ 2 OCH;C-OCH CHgN 5 01115 a CH -01; OH

2 2" I I CH3 a I v I I N /CH H H V UHF H: N

\OH H (7) o o-oHni-NH, 011,-011, I N QHf-CH,

GH-CH, 5

0235 7 CHF H2 CH:CHg-CH1 I H noxy acetates which can then be convertedto any desired esters or amides, in accordance-with conventionalprocedures. Equations for the foregoing preparations are as follows,with X being halogen The acetate ester thus obtained can be hydrolyzedto form the acid, can be transesterified with an alcohol of the formulaR OH' to form the appropriate ester, can be reacted to form amides withammonia and with primary or secondary amines, and with hydrazines. In analternative procedure, the compounds of this invention can be preparedby condensing a nitrophenol with an ethyl-alphahalo alkanoate, reducingthe resultant nitrophenoxy acetate to the aminophenoxy acetate andcyclizing the amino group to form a heterocyclic group. Reduction andring closure can take place either prior to or after esterification oramide formation. An equation for this preparae tion is as follows:

(8) I R1 (l l) OH w OH-OOCgHg NO:+X-CHCOOC3H3 (b) R1 R! (I) odH-iiocm,ohm-doom,

. [H] N03 NH;

with further procedure as Preparation I.

An alternative method of preparing the heteroaminophenols which can beused in Preparation I consists of 12 ring closure with ortho, meta orpara anisidine followed by cleavage of the ether with hydriodic acid.This procedure can be illustrated as follows:

(a) con: I 0on3 NH; XZ--X N (b) O CH:

N HI N The resultant compounds can be reacted with any pharmaceuticallyacceptable inorganic or organic acid to form non-toxicpharmacologi-cally acceptable acid addition salts such ashydrochlorides, hydrobromides, nitrates, sulfates, phosphates, acetates,formates, tartrates, m-alates, theophyllinates,8-chloroetheophyllinates, and the like. Similarly, through the use ofselected quaternizing agents, such as alkyl sulfates and alkyl halides,e.g., methyl iodide, ethyl bromide, methyl p-toluene-sulfonate, allylbromide, ethyl bromoacetate, and the like, non-toxic pharmacologicallyacceptable quaternary salts of the novel compounds are readily prepared.

These quaternary salts can be represented by the formula Br (I) whereinR is selected from the group consisting of hydrogen and an organicradical having from one to eight carbon atoms such as methyl, ethyl,propyl, butyl, octyl, a-llyl, pentyl, benzyl and carboethoxyalkyl suchas carboethoxymethyl, and A is an inert' non-toxic pharmacologicallyacceptable anion, such as bromide, iodide, chloride andp-toluenesulfonate.

When R contains a nitrogen atom, the quaternary salt can be formed atthat nitrogen atom or at both the R nitnogen atom and the heterocyclicnitrogen atom.

The quaternary ammonium salts can be prepared by conventional methods asby refluxing equivalent quantities of the appropriate amino substitutedphenoxyacetic acid with an alkyl halide or an alkyl sulfate in an inertsolvent such as ethanol or benzene. The quaternary ammonium saltsgenerally crystallize out on standing. Where crystallization does notoccur, the solution can be cooled or an additional hydrocarbon solventsuch as hexane can be added in accordance with conventional techniques.Where the double quaternary salt is desired, two equivalents of thealkyl halide or alkyl or alkyl sulfate can be added.

The acid addition salts are prepared by reacting equivalent quantitiesof the amino substituted phenoxyacetic acid and the desired acid in aninert solvent such as ethanol or benzene and recovering the acidaddition salt by conventional means.

The following working examples illustrate the best modes of preparingthe compounds of this invention.

EXAMPLE I A mixture of 102 g. (0.84 mole) of o-anisidine, g. (0.84 mole)of 1,4-dibromobutane, 172 g. (1.12 mole) of sodium carbonate and 900 mlsof aoetonitrile were refluxed with stirring for 34 hours. Afterfiltering off the salts, the solution was evaporated down and theresidue taken up in dilute hydrochloric acid. The solution was 13 washedwith ether, then made basic with dilute sodium hydroxide and theresulting oil extracted into three portions of ether. These werecombined, dried over anhydrous magnesium sulfate, then filtered, thesolvent evaporated off and the residue distilled to give 103 g. ofo-(lpyrrolidinyl)anisole, boiling at 127-130 at mm. gm. of theo-(1-pyrrolidinyl)anisole so prepared and 50 ml. of constant boilinghydriodic acid were refluxed together for 28 hours, permitting methyliodide to distill out as formed. At the end of this time, the hydriodicacid was removed at. diminished pressure leaving a clear, thick oil.This was dissolved in water, the solution rnade basic with a saturated,aqueous solution of sodium bicarbonate and the resulting precipitatefiltered off to yield o-(lpyrrolidinyl)phenol, melting at 109-111". 21.2g. (0.13 mole) of this o-(l-pyrrolidinyl)phenol, 21.8 g. (0.13 mole) ofethyl bromoacetate, 18.5 g. (0.13 mole) of potassium carbonate and 200ml. of acetone were refluxed with stirring for 40 hours. The solids werethen filtered off, the filtrate evaporated down to a thick oil and thisoil dissolved in benzene. This solution was extracted with severalportions of dilute hydrochloric acid, and the resulting aqueous solutionmade basic again with 40% aqueous sodium hydroxide to yield an oil whichwas taken up in ether. The ethereal solution was then dried overanhydrous magnesium sulfate, the drying agent filtered off, the etherremoved and the residue distilled to give 26 g. ofethyl-a-[o-(1-pyrrolidinyl)phenoxy] acetate, boiling at 136-l39 C. at0.25 mm. n =1.5465.

Anal.-Calc. for C H NO C, 67.4; H, 7.7; N, 5.6. Found: C, 67.2; H, 7.6;N, 5.3.

EXAMPLE II 3-dimethylaminopropylamine (7.5 g., 0.075 mole), 3.8 g.(0.015 mole) of ethyl-a-[-o-(1-pyrrolidinyl)phenoxy] acetate and 10drops of 25% methanolic sodium methylate were heated in an oil bath at140 C. for a total of 17 hours. From time to time, the bath was raisedto 160 C. to distill out the ethanol formed. After cooling, pentane wasadded to the reaction mixture and a small quantity of insoluble materialfiltered off. The pentane filtrate was then evaporated down with theexcess 3-dimethylaminopropylamine being distilled 011. The productremaining which boiled at 178182 C. at 0.005 mm. (n =1.5474), wasidentified as a-[o-(1-pyrrolidinyl)phenoxy]-N-(3-dimethylaminopropyl)acetamide.

EXAMPLE III A solution of 33.4 g. (0.2 m.) of ethyl bromoacetate in 50mls. of acetone was slowly added to a stirred mixture of 27.4 g. (0.2m.) of m-nitrophenol, 27.6 g. anhydrous potassium carbonate and 150 mls.of acetone. After refluxing and stirring for 7 hours, the solid wasfiltered 01f, solvent evaporated off from the filtrate and the residuedistilled to give 41.9 g. (93%) of ethyI-Z-(m-nitrophenoxy)acetate. Asolution of 41.9 g. (0.19 m.) of the ethyl 2 (m-nitrophenoxy)acetate in208 mls. of ethanol with 0.3 g. of platinum oxide was hydrogenated in aParr hydrogenator at an initial pressure of 3 atmospheres. Hy.- drogenuptake was complete (105%) after 70 minutes of shaking. After removalfrom the hydrogenator and filtration, the solvent was removed atdiminished pressure, the residue taken up in dry ether and treated with.dry hydrogen chloride. Filtration yielded 38 g. melting at 1 25 135.Recrystallization from acetonitrile gave 33 g. of ethylZ-(m-aminophenoxy) acetate hydrochloride. A mixture of 8.0 g. (0.034 m.)of the ethyl Z-(m-aminophenoxy) acetate hydrochloride and 5.4 g. (0.051in.) of anhydrous sodium carbonate and 30 mls. of acetonitrile was addedwhile a solution of 7.4 g. (0.034 m.) of 1,4-dibromo1 butane in 20 mls.of acetonitrile was slowly added. Stirring was continued while refluxingfor 27 hours. tion, removal of solvent and distillation. gave 5.9 g.(70%) of product, boiling at 150-154 at 0.2 mm. The distillatesolidified slowly on cooling to give a low melting Filtra- 14 solididentified as ethyl 2-(m-pyrrolidinylphenoxy) acetate. Anal.Calc. for CH NO N, 5.6. Found: N, 5.4.

EXAMPLE IV By following the procedure set forth in Example III, butusing 1,5-dibromopentane in place of 1,4-dibromobutane, thecorresponding piperidiny-l derivative, ethyl 2-(m-piperidinylphenoxy)acetate, was obt-ained.

EXAMPLE V Additional compounds were prepared in accordance with theprocedure of Examples I and II. The melting points of representativecompounds are listed in Table I:

Table I Compound No. (as listed above) Recrystallization Melting SolventPoint C.) 1

2 Acetonitrile 133-134 3 Hexane 61- 62 7 Ethanol 156 8 Hexane 96- 99 12Isopropmol 134-137 13 do 109-111 17 ..(10 148-150 18 Hexane 101-102 19do 113-116 20 do 78- 81 22 Ethanol 57- 58 23 Methanol 211 24 Ethanol 17525 Hexane 97- 98 28 Ethanol 164 29 Heptane 33 Ethanol 161 4 34 Heptane144 37 Hexane 88- 89 41 do 88- 89 42 do 63- 64 points and/or refractiveindices of representative compounds are listed in Table II.

Table 11 Compound No. (as listed above) Boiling Pressure, o

Point, C. mm.

The compounds of this invention can be used to reduce the cholesterollevel of blood either directly or preferably by incorporating into ahypocholesteremic composition.

Inaddition to the heterocyclic amino phenoxyacetic acid compound, thehypocholesteremic compositions of the or parenterally. By such methodsthese compositions have.

the ability to markedlyreduce the cholesterol level of blood in animals.The toxicity of these compounds is quite low, and the active ingredientcan be administered in dosages adequate to obtain a therapeutic effectwithout adverse side effects. The concentration of the phenoxyaceticacid compound in these compositions is not in any way critical, but canbe adjusted to meet the need. In general, the concentration for oral andparenteral administration will lie within about 1 to about 300 mg. perunit dosage, i.e., per cc. of solution or per tablet or capsule,depending upon the dosage regimen desired and the weight andhypocholesteremic state of the animal. Ordinarily, it is preferable toadminister a composition having a low concentration of the activeingredient several times daily, as compared to a single daily dosehaving a relatively high concentration of the active ingredient, toachieve the total daily dosage required. The daily dosage is generallywithin the range of about 25 to about 300 mg. of acid compound.

In the process of the invention, the heterocyclic amino phenoxyaceticacid compound or mixture thereof in an appropriate amount to obtain atherapeutic effect is administered to the patient orally, parenterallyor by any other appropriate method, and there results ahypocholesteremic response.

The examples illustrate various types of compositions coming within theinvention for a variety of administration techniques.

EXAMPLE VII A composition of matter for oral administration, comprisingethyl o-(l-pyrrolidinyl)phenoxy acetate acid as the active ingredient incombination with a suitable carrier, was prepared by thoroughly mixingtogether 1000 grams of the active compound and 3500 grams of betalactose(milk sugar), passing the blended mixture through a No. 40 screen andfilling the mix into gelatin capsules, 450 mg. per capsule, each capsuleto contain 100 mg. of active ingredient.

EXAMPLE VIII A composition of matter for oral administration, in tabletform, comprising cyclohexyl (m-l-pyrrolidinyl) phenoxy isopropionate asthe active ingredient in combination with a suitable carrier, wasprepared by compounding the following ingredients into a tablet mix:

Grams Active ingredient 308 Sugar 308 Lactose 177 Starch 98 Dextrin 50Talcum l Stearic acid 10 Starch paste q.s. to make 1000.

The above mix was comphessed into tablets, weighing approximately 325mg., each tablet containing 100 mg. of active ingredient.

EXAMPLE IX A composition of matter for parenteral administrationcomprising m-(l-pyrrolidinyl) phenoxy methylacetamide as the activeingredient in combination with a liquid carrier having the followingformula was prepared:

Grams Active ingredient 25 Sodium hydroxide 5.74 Benzyl alcohol 5 underExamples V, VI and VII may be made by including other substances havingtherapeutic properties which enhance the total therapeutic value of theheterocyclic amino phenoxyacetic acid compound by their additive or by asynergistic effect; the effect, if synergistic, will enhance thetherapeutic value of the heterocyclic amino phenoxyacetic compoundwithout increase in dosage. Thus, known therapeutic substances, such asaspirin or equivalent salicylate compound, may be added for theiranalgesic and anti-rheumatic effect, butazolidin or antipyrine orrelated compounds for their anti-pyretic and anti-phlogistic effects,hydrocortisone or prednisolone or one of its equivalent corticosteroidsfor their anti-rheumatic, antiinflammatory and anti-phlogistic effects.The combination of a heterocyclic amino phenoxyacetic acid compound withone or more of the above additive substances also serves the purpose ofan additive effect.

If desired, other substances, such as ascorbic acid, vitamin K,thiamine, etc., may be added to the composition of matter in adequatedosage to exert their individual activity for therapeutic uses they areknown to have.

If desired, the hypocholesteremic compositions can be sterilized and cancontain auxiliary substances such as buffering lagents, stabilizingagents, wetting agents and emulsifying agents.

To illustrate the therapeutic utility of the compounds of this inventionin reducing the cholesterol level of blood, normal adult guinea pigswere given subcutaneous doses corresponding to 30 mg./ kg. of the testcompound at the beginning of the experiment, 24 hours later and finally,40 hours later.

Blood samples Were drawn for the determination of serum cholesterollevels at the initiation of the experiment and at 48, and 72 hoursthereafter.

The hypocholsteremic response is indicated in Table III.

In this table, the compound is identified by its number in the listabove. The LD indicates the minimum dose which is lethal to mice whenthe compound is administered subcutaneously and is expressed in mg./kg.The dose is the dosage of the drug administered subcutaneously expressedmg./kg. under the schedule described above and the effect of thecompound in reducing cholesterol is indicated by the percent reductionfrom the cholesterol level noted for the animal at the initiation of theexperiment (percent 'hypocholesteremia).

Thus, if at the initiation of the experiment the noted cholesterol levelwas 80 mg. percent and at a subsequent interval, the noted cholesterollevel was 60 mg. percent, this would be shown as 25% hypocholesteremia.

Table III HYPOCHOLESTEREMIC EFFECT OF REPRESENTATIVE COMPO UNDS PercentHypoeho- L mM lesteremia Compound No. mg./kg.s.c.

48 hrs. 72 hrs.

'rapid and sustained overall hypocholesteremic response.

It is evident from Table III that the compounds of this invention showsubstantial hypocholesteremic activity at dosage levels substantiallybelow the minimum lethal doses. Aconsiderable reduction of cholesterollevels is 17 obtained at substantially of the LD for many of thecompounds.

Under clinical conditions the rapidity of the depression of cholesterollevels obtained in the tests reported above would not be required sothat even smaller doses could be used, thereby increasing the margin ofsafety.

The compounds of this invention in addition to their hypocholesteremicactivity are also useful intermediates in the production of othercompounds and also have utility as muscle relaxants andanti-inflammatory agents.

We claim:

1. A compound selected from the group consisting of those having theformula wherein R is selected from the group consisting of hydrogen andlower alkyl, and

is selected from the group consisting of X-pyrrolidino, X- piperidino,X-hexamethyleneimino, X-morpholino, X-

'thiomorpholino, and X-oct-amethyleneimino, wherein X is selected fromthe group consisting of hydrogen, lower alkyl, hydroxy and acetyl; andthe non-toxic acid addition salts and quaternary ammonium salts thereof.

2. A compound in accordance with claim 1 wherein is pyrrolidino.

3. A compound in accordance with claim 1 wherein References Cited by theExaminer UNITED STATES PATENTS is piperidino.

NICHOLAS S. RIZZO, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,218,328 November 16, 1965 Seymour L. Shapiro, deceased, by Florence M.Shapiro, as executrix, et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 4, lines 44 to 50, formula (5) should appear as shown belowinstead of as in the patent:

O-CH C-OC H CH -CH column 7, lines 44 to 54, formula (30] should appearas shown below instead of as in the patent:

3 H 3 CH NHCH2CH2-CH2N /CH2- H2 I\\ column 10, lines 35 to 43, formula(52) should appear as shown below instead of as in the patent:

same column 10, lines 55 to 62, formula (54) should appear as shownbelow instead of as in the patent:

H -CH N CH H column 15, line 52, for "comphessed" read compressed Signedand sealed this 27th day of September 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULA
 3. A COMPOUND IN ACCORDANCE WITH CLAIM 1 WHEREIN